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Midodrine

PubChem CID
4195
Structure
Midodrine_small.png
Midodrine_3D_Structure.png
Molecular Formula
Synonyms
  • midodrine
  • 42794-76-3
  • Midodrin
  • Midodrinum
  • Midodrina
Molecular Weight
254.28 g/mol
Computed by PubChem 2.2 (PubChem release 2024.11.20)
Dates
  • Create:
    2005-03-25
  • Modify:
    2024-12-27
Description
Midodrine is an aromatic ether that is 1,4-dimethoxybenzene which is substituted at position 2 by a 2-(glycylamino)-1-hydroxyethyl group. A direct-acting sympathomimetic with selective alpha-adrenergic agonist activity, it is used (generally as its hydrochloride salt) as a peripheral vasoconstrictor in the treatment of certain hypotensive states. The main active moiety is its major metabolite, deglymidodrine. It has a role as a prodrug, an alpha-adrenergic agonist, a sympathomimetic agent and a vasoconstrictor agent. It is a secondary alcohol, an amino acid amide and an aromatic ether. It is functionally related to a glycinamide and a deglymidodrine. It is a conjugate base of a midodrine(1+).
An ethanolamine derivative that is an adrenergic alpha agonist. It is used as a vasoconstrictor agent in the treatment of hypotension.
Midodrine is an alpha-Adrenergic Agonist. The mechanism of action of midodrine is as an Adrenergic alpha-Agonist.

1 Structures

1.1 2D Structure

Chemical Structure Depiction
Midodrine.png

1.2 3D Conformer

2 Names and Identifiers

2.1 Computed Descriptors

2.1.1 IUPAC Name

2-amino-N-[2-(2,5-dimethoxyphenyl)-2-hydroxyethyl]acetamide
Computed by Lexichem TK 2.7.0 (PubChem release 2024.11.20)

2.1.2 InChI

InChI=1S/C12H18N2O4/c1-17-8-3-4-11(18-2)9(5-8)10(15)7-14-12(16)6-13/h3-5,10,15H,6-7,13H2,1-2H3,(H,14,16)
Computed by InChI 1.07.0 (PubChem release 2024.11.20)

2.1.3 InChIKey

PTKSEFOSCHHMPD-UHFFFAOYSA-N
Computed by InChI 1.07.0 (PubChem release 2024.11.20)

2.1.4 SMILES

COC1=CC(=C(C=C1)OC)C(CNC(=O)CN)O
Computed by OEChem 2.3.0 (PubChem release 2024.11.20)

2.2 Molecular Formula

C12H18N2O4
Computed by PubChem 2.2 (PubChem release 2024.11.20)

2.3 Other Identifiers

2.3.1 CAS

133163-28-7

2.3.3 Deprecated CAS

97476-58-9

2.3.4 European Community (EC) Number

2.3.5 UNII

2.3.6 ChEBI ID

2.3.7 ChEMBL ID

2.3.8 DrugBank ID

2.3.9 DSSTox Substance ID

2.3.10 HMDB ID

2.3.11 KEGG ID

2.3.12 Metabolomics Workbench ID

2.3.13 NCI Thesaurus Code

2.3.14 Nikkaji Number

2.3.15 PharmGKB ID

2.3.16 Pharos Ligand ID

2.3.17 RXCUI

2.3.18 Wikidata

2.3.19 Wikipedia

2.4 Synonyms

2.4.1 MeSH Entry Terms

  • Amatine
  • Gutron
  • Midodrin
  • Midodrine
  • Midodrine Hydrochloride
  • Midodrine Monohydrochloride
  • Midon
  • Monohydrochloride, Midodrine
  • ProAmatine
  • ST 1085
  • ST-1085
  • ST1085

2.4.2 Depositor-Supplied Synonyms

3 Chemical and Physical Properties

3.1 Computed Properties

Property Name
Molecular Weight
Property Value
254.28 g/mol
Reference
Computed by PubChem 2.2 (PubChem release 2024.11.20)
Property Name
XLogP3-AA
Property Value
-0.6
Reference
Computed by XLogP3 3.0 (PubChem release 2024.11.20)
Property Name
Hydrogen Bond Donor Count
Property Value
3
Reference
Computed by Cactvs 3.4.8.18 (PubChem release 2024.11.20)
Property Name
Hydrogen Bond Acceptor Count
Property Value
5
Reference
Computed by Cactvs 3.4.8.18 (PubChem release 2024.11.20)
Property Name
Rotatable Bond Count
Property Value
6
Reference
Computed by Cactvs 3.4.8.18 (PubChem release 2024.11.20)
Property Name
Exact Mass
Property Value
254.12665706 Da
Reference
Computed by PubChem 2.2 (PubChem release 2024.11.20)
Property Name
Monoisotopic Mass
Property Value
254.12665706 Da
Reference
Computed by PubChem 2.2 (PubChem release 2024.11.20)
Property Name
Topological Polar Surface Area
Property Value
93.8Ų
Reference
Computed by Cactvs 3.4.8.18 (PubChem release 2024.11.20)
Property Name
Heavy Atom Count
Property Value
18
Reference
Computed by PubChem
Property Name
Formal Charge
Property Value
0
Reference
Computed by PubChem
Property Name
Complexity
Property Value
262
Reference
Computed by Cactvs 3.4.8.18 (PubChem release 2024.11.20)
Property Name
Isotope Atom Count
Property Value
0
Reference
Computed by PubChem
Property Name
Defined Atom Stereocenter Count
Property Value
0
Reference
Computed by PubChem
Property Name
Undefined Atom Stereocenter Count
Property Value
1
Reference
Computed by PubChem
Property Name
Defined Bond Stereocenter Count
Property Value
0
Reference
Computed by PubChem
Property Name
Undefined Bond Stereocenter Count
Property Value
0
Reference
Computed by PubChem
Property Name
Covalently-Bonded Unit Count
Property Value
1
Reference
Computed by PubChem
Property Name
Compound Is Canonicalized
Property Value
Yes
Reference
Computed by PubChem (release 2021.10.14)

3.2 Experimental Properties

3.2.1 Physical Description

Solid

3.2.2 Melting Point

200to 203°C
150 °C
O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Whitehouse Station, NJ: Merck and Co., Inc., 2006., p. 1067
200 - 203 °C

3.2.3 Solubility

Soluble
4.45e+00 g/L

3.2.4 LogP

-0.5
-0.5

3.2.5 Optical Rotation

Specific optical rotation = +138.5 deg at 20 °C/D (concentration = 0.5 in chloroform)
O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Whitehouse Station, NJ: Merck and Co., Inc., 2006., p. 1067

3.2.6 Decomposition

When heated to decomposition, material emits toxic fumes of nitrogen oxides and hydrogen chloride.
United States Pharmacopeial Convention, Inc (USP); MSDS Database Online; Material Safety Data Sheet: Midodrine Hydrochloride; Catalog Number: 1443704; (Revision Date: January 19, 2010)

3.2.7 Dissociation Constants

pKa
7.8
pKa = 7.8 (0.3% aqueous solution); pH 3.5 to 5.5 (5% aqueous solution) /Midodrine hydrochloirde/
Wishart DS et al; DrugBank: a knowledgebase for drugs, drug actions and drug targets. Nucleic Acids Res. 2008 Jan;36(Database issue):D901-6. Available from, as of Sept 13, 2010: https://www.drugbank.ca

3.2.8 Collision Cross Section

160.41 Ų [M+K]+ [CCS Type: TW; Method: calibrated with polyalanine and drug standards]

151.8 Ų [M+H]+ [CCS Type: TW; Method: calibrated with polyalanine and drug standards]

153.21 Ų [M+H-H2O]+ [CCS Type: TW; Method: calibrated with polyalanine and drug standards]

160.34 Ų [M+Na]+ [CCS Type: TW; Method: calibrated with polyalanine and drug standards]

Ross et al. JASMS 2022; 33; 1061-1072. DOI:10.1021/jasms.2c00111

3.2.9 Other Experimental Properties

White to off-white /Midodrine hydrochloride/
SRI Consulting, 2010 Directory of Chemical Producers. Menlo Park, CA. 2010, p. 2334

3.3 Chemical Classes

3.3.1 Drugs

Pharmaceuticals
S10 | SWISSPHARMA | Pharmaceutical List with Consumption Data | DOI:10.5281/zenodo.2623484
3.3.1.1 Human Drugs
Human drug -> Discontinued
Pharmaceuticals
S72 | NTUPHTW | Pharmaceutically Active Substances from National Taiwan University | DOI:10.5281/zenodo.3955664

5 Chemical Vendors

6 Drug and Medication Information

6.1 Drug Indication

For the treatment of symptomatic orthostatic hypotension (OH).

6.2 Clinical Trials

6.2.1 ClinicalTrials.gov

6.2.2 EU Clinical Trials Register

6.3 Therapeutic Uses

FDA proposed to withdraw approval of the drug midodrine hydrochloride, used to treat the low blood pressure condition, orthostatic hypotension, because required post-approval studies that verify the clinical benefit of the drug have not been done. To date, neither the original manufacturer nor any generic manufacturer has demonstrated the drug's clinical benefit, for example, by showing that use of the drug improved a patient's ability to perform life activities.
FDA; MedWatch The FDA Safety Information and Adverse Event Reporting Program; Midodrine hydrochloride: FDA Proposes Withdrawal of Low Blood Pressure Drug, last updated September 10, 2010. Available from, of November 17, 2010: https://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm222640.htm
...used as a vasoconstrictor agent in the treatment of hypotension
Wishart DS et al; DrugBank: a knowledgebase for drugs, drug actions and drug targets. Nucleic Acids Res. 2008 Jan;36(Database issue):D901-6. Available from, as of Sept 13, 2010: https://www.drugbank.ca
Midodrine hydrochloride is used in the management of symptomatic orthostatic hypotension; the drug is designated an orphan drug by the US Food and Drug Administration (FDA) for such use. /Included in US product label/
American Society of Health System Pharmacists; AHFS Drug Information 2010. Bethesda, MD. (2010), p. 1305

6.4 Drug Warnings

WARNING: Because midodrine hydrochloride tablets can cause marked elevation of supine blood pressure, it should be used in patients whose lives are considerably impaired despite standard clinical care. The indication for use of midodrine hydrochloride tablets in the treatment of symptomatic orthostatic hypotension is based primarily on a change in a surrogate marker of effectiveness, an increase in systolic blood pressure measured one minute after standing, a surrogate marker considered likely to correspond to a clinical benefit. At present, however, clinical benefits of midodrine hydrochloride tablets, principally improved ability to carry out activities of daily living, have not been verified.
US Natl Inst Health; DailyMed. Current Medication Information for MIDODRINE HCL (midodrine hydrochloride) tablet (October 2010). Available from, as of November 17, 2010: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?id=31527
The most potentially serious adverse reaction associated with midodrine hydrochloride therapy is marked elevation of supine arterial blood pressure (supine hypertension). Systolic pressure of about 200 mmHg was seen overall in about 13.4% of patients given 10 mg of midodrine hydrochloride. Systolic elevations of this degree were most likely to be observed in patients with relatively elevated pre-treatment systolic blood pressures (mean 170 mmHg). There is no experience in patients with initial supine systolic pressure above 180 mmHg, as those patients were excluded from the clinical trials. Use of midodrine hydrochloride in such patients is not recommended. Sitting blood pressures were also elevated by midodrine hydrochloride therapy. It is essential to monitor supine and sitting blood pressures in patients maintained on midodrine hydrochloride.
US Natl Inst Health; DailyMed. Current Medication Information for MIDODRINE HCL (midodrine hydrochloride) tablet (October 2010). Available from, as of November 17, 2010: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?id=31527
The potential for supine and sitting hypertension should be evaluated at the beginning of midodrine hydrochloride therapy. Supine hypertension can often be controlled by preventing the patient from becoming fully supine, i.e., sleeping with the head of the bed elevated. The patient should be cautioned to report symptoms of supine hypertension immediately. Symptoms may include cardiac awareness, pounding in the ears, headache, blurred vision, etc.
US Natl Inst Health; DailyMed. Current Medication Information for MIDODRINE HCL (midodrine hydrochloride) tablet (October 2010). Available from, as of November 17, 2010: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?id=31527
Midodrine hydrochloride use has not been studied in patients with hepatic impairment. Midodrine hydrochloride should be used with caution in patients with hepatic impairment, as the liver has a role in the metabolism of midodrine.
US Natl Inst Health; DailyMed. Current Medication Information for MIDODRINE HCL (midodrine hydrochloride) tablet (October 2010). Available from, as of November 17, 2010: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?id=31527
For more Drug Warnings (Complete) data for Midodrine (12 total), please visit the HSDB record page.

7 Pharmacology and Biochemistry

7.1 Pharmacodynamics

Midodrine is a prodrug, i.e., the therapeutic effect of orally administered midodrine is due to the major metabolite desglymidodrine formed by deglycination of midodrine. Administration of midodrine results in a rise in standing, sitting, and supine systolic and diastolic blood pressure in patients with orthostatic hypotension of various etiologies. Standing systolic blood pressure is elevated by approximately 15 to 30 mmHg at 1 hour after a 10-mg dose of midodrine, with some effect persisting for 2 to 3 hours. Midodrine has no clinically significant effect on standing or supine pulse rates in patients with autonomic failure.

7.2 MeSH Pharmacological Classification

Vasoconstrictor Agents
Drugs used to cause constriction of the blood vessels. (See all compounds classified as Vasoconstrictor Agents.)
Adrenergic alpha-1 Receptor Agonists
Compounds that bind to and activate ADRENERGIC ALPHA-1 RECEPTORS. (See all compounds classified as Adrenergic alpha-1 Receptor Agonists.)
Sympathomimetics
Drugs that mimic the effects of stimulating postganglionic adrenergic sympathetic nerves. Included here are drugs that directly stimulate adrenergic receptors and drugs that act indirectly by provoking the release of adrenergic transmitters. (See all compounds classified as Sympathomimetics.)

7.3 FDA Pharmacological Classification

FDA UNII
6YE7PBM15H
Active Moiety
MIDODRINE
Pharmacological Classes
Mechanisms of Action [MoA] - Adrenergic alpha-Agonists
Pharmacological Classes
Established Pharmacologic Class [EPC] - alpha-Adrenergic Agonist
FDA Pharmacology Summary
Midodrine is an alpha-Adrenergic Agonist. The mechanism of action of midodrine is as an Adrenergic alpha-Agonist.

7.4 ATC Code

C - Cardiovascular system

C01 - Cardiac therapy

C01C - Cardiac stimulants excl. cardiac glycosides

C01CA - Adrenergic and dopaminergic agents

C01CA17 - Midodrine

7.5 Absorption, Distribution and Excretion

Absorption
Rapidly absorbed following oral administration. The peak plasma concentrations of the prodrug, desglymidodrine, is reached about half an hour following drug administration. The metabolites reach their peak plasma concentrations at about 1 to 2 hours following drug administration. The absolute bioavailability of midodrine (measured as desglymidodrine) is 93% and is not affected by food. As desglymidodrine displays poor diffusibility across the blood-brain barrier, it is expected to have minimal effects on the central nervous system.
Clearance
Renal cl=385 mL/minute
Renal elimination of midodrine is insignificant. The renal clearance of desglymidodrine is of the order of 385 mL/minute, most, about 80%, by active renal secretion. The actual mechanism of active secretion has not been studied, but it is possible that it occurs by the base-secreting pathway responsible for the secretion of several other drugs that are bases.
US Natl Inst Health; DailyMed. Current Medication Information for MIDODRINE HCL (midodrine hydrochloride) tablet (October 2010). Available from, as of November 17, 2010: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?id=31527
Midodrine hydrochloride is a prodrug, i.e., the therapeutic effect of orally administered midodrine is due to the major metabolite desglymidodrine, formed by deglycination of midodrine. After oral administration, midodrine hydrochloride is rapidly absorbed. The plasma levels of the prodrug peak after about half an hour and decline with a half-life of approximately 25 minutes, while the metabolite reaches peak blood concentrations about 1 to 2 hours after a dose of midodrine and has a half-life of about 3 to 4 hours. The absolute bioavailability of midodrine (measured as desglymidodrine) is 93%. The bioavailability of desglymidodrine is not affected by food. Approximately the same amount of desglymidodrine is formed after intravenous and oral administration of midodrine. Neither midodrine nor desglymidodrine is bound to plasma proteins to any significant extent.
US Natl Inst Health; DailyMed. Current Medication Information for MIDODRINE HCL (midodrine hydrochloride) tablet (October 2010). Available from, as of November 17, 2010: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?id=31527
Midodrine is an oral drug for orthostatic hypotension. This drug is almost completely absorbed after oral administration and converted into its active form, 1-(2',5'-dimethoxyphenyl)-2-aminoethanol) (DMAE), by the cleavage of a glycine residue. The intestinal H+-coupled peptide transporter 1 (PEPT1) transports various peptide-like drugs and has been used as a target molecule for improving the intestinal absorption of poorly absorbed drugs through amino acid modifications. Because midodrine meets these requirements, we examined whether midodrine can be a substrate for PEPT1. The uptake of midodrine, but not DMAE, was markedly increased in PEPT1-expressing oocytes compared with water-injected oocytes. Midodrine uptake by Caco-2 cells was saturable and was inhibited by various PEPT1 substrates. Midodrine absorption from the rat intestine was very rapid and was significantly inhibited by the high-affinity PEPT1 substrate cyclacillin, assessed by the alteration of the area under the blood concentration-time curve for 30 min and the maximal concentration. Some amino acid derivatives of DMAE were transported by PEPT1, and their transport was dependent on the amino acids modified. In contrast to neutral substrates, cationic midodrine was taken up extensively at alkaline pH, and this pH profile was reproduced by a 14-state model of PEPT1, which we recently reported. These findings indicate that PEPT1 can transport midodrine and contributes to the high bioavailability of this drug and that Gly modification of DMAE is desirable for a prodrug of DMAE.
Tsuda M et al; J Pharmacol Exp Ther 318 (1): 455-60 (2006)

7.6 Metabolism / Metabolites

Thorough metabolic studies have not been conducted, but it appears that deglycination of midodrine to desglymidodrine takes place in many tissues, and both compounds are metabolized in part by the liver.
The human cytochrome P450 (CYP) isoforms catalyzing the oxidation metabolism of desglymidodrine (DMAE), an active metabolite of midodrine, were studied. Recombinant human CYP2D6, 1A2 and 2C19 exhibited appreciable catalytic activity with respect to the 5'-O-demethylation of DMAE. The O-demethylase activity by the recombinant CYP2D6 was much higher than that of other CYP isoforms. Quinidine (a selective inhibitor of CYP2D6) inhibited the O-demethylation of DMAE in pooled human microsomes by 86%, while selective inhibitors for other forms of CYP did not show any appreciable effect. Although the activity of CYP2D6 was almost negligible in the PM microsomes, the O-demethylase activity of DMAE was found to be maintained by about 25% of the pooled microsomes. Furafylline (a selective inhibitor of CYP1A2) inhibited the M-2 formation in the PM microsomes by 57%. The treatment of pooled microsomes with an antibody against CYP2D6 inhibited the formation of M-2 by about 75%, whereas that of the PM microsomes did not show drastic inhibition. In contrast, the antibody against CYP1A2 suppressed the activity by 40 to 50% in the PM microsomes. These findings suggest that CYP2D6 have the highest catalytic activity of DMAE 5'-O-demethylation in human liver microsomes, followed by CYP1A2 to a small extent.
Akimoto M et al; Eur J Drug Metab Pharmacokinet 29 (3): 179-86 (2004)
Thorough metabolic studies have not been conducted, but it appears that deglycination of midodrine to desglymidodrine takes place in many tissues and both compounds are metabolized in part by the liver. Neither midodrine nor desglymidodrine is a substrate for monoamine oxidase.
US Natl Inst Health; DailyMed. Current Medication Information for MIDODRINE HCL (midodrine hydrochloride) tablet (October 2010). Available from, as of November 17, 2010: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?id=31527

7.7 Biological Half-Life

The metabolites display a half-life of about 3 to 4 hours.
The plasma levels of the prodrug peak after about half an hour and decline with a half-life of approximately 25 minutes, while the metabolite reaches peak blood concentrations about 1 to 2 hours after a dose of midodrine and has a half-life of about 3 to 4 hours.
US Natl Inst Health; DailyMed. Current Medication Information for MIDODRINE HCL (midodrine hydrochloride) tablet (October 2010). Available from, as of November 17, 2010: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?id=31527

7.8 Mechanism of Action

Midodrine undergoes metabolism to form its pharmacologically active metabolite, desglymidodrine. Desglymidodrine acts as an agonist at the alpha1-adrenergic receptors expressed in the arteriolar and venous vasculature. Activation of alpha1-adrenergic receptor signaling pathways lead to an increase in the vascular tone and elevation of blood pressure. Desglymidodrine is reported to have negligible effect on the cardiac beta-adrenergic receptors.
Midodrine hydrochloride forms an active metabolite, desglymidodrine, that is an alpha1-agonist and exerts its actions via activation of the alpha-adrenergic receptors of the arteriolar and venous vasculature, producing an increase in vascular tone and elevation of blood pressure. Desglymidodrine does not stimulate cardiac beta-adrenergic receptors. Desglymidodrine diffuses poorly across the blood-brain barrier and is therefore not associated with effects on the central nervous system.
US Natl Inst Health; DailyMed. Current Medication Information for MIDODRINE HCL (midodrine hydrochloride) tablet (October 2010). Available from, as of November 17, 2010: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?id=31527

7.9 Human Metabolite Information

7.9.1 Cellular Locations

Membrane

8 Use and Manufacturing

8.1 Uses

MEDICATION

<b>Use (kg; approx.) in Germany (2009):</b> >10

<b>Consumption (g per capita; approx.) in Germany (2009):</b> 0.000122

<b>Calculated removal (%):</b> 45.4

8.1.1 Use Classification

Pharmaceuticals
S72 | NTUPHTW | Pharmaceutically Active Substances from National Taiwan University | DOI:10.5281/zenodo.3955664

8.2 Methods of Manufacturing

Synthesized from hydroquinone dimethyl ether by Friedel-Crafts acylation with chloroacetyl chloride, amination to the corresponding 2-aminoacetophenone, acylation at the amino function with chloroacetyl chloride, displacement of the chloro by the azido group and finally reduction with, e.g., sodium borohydride and catalytic hydrogenation (Pd/C).
Kleemann A; Ullmann's Encyclopedia of Industrial Chemistry. 7th ed. (2008). New York, NY: John Wiley & Sons; Cardiovascular Drugs. Online Posting Date: 15 Jan 2008.

8.3 Formulations / Preparations

Table: Midodrine Hydrochloride Preparations
Route of Administration
Oral
Dosage Form
Tablets
Strength
2.5 mg
Brand or Generic Name (Manufacturer)
Midodrine Hydrochloride Tablets (Available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name)
Route of Administration
Oral
Dosage Form
Tablets
Strength
2.5 mg
Brand or Generic Name (Manufacturer)
Orvaten (Upsher-Smith)
Route of Administration
Oral
Dosage Form
Tablets
Strength
2.5 mg
Brand or Generic Name (Manufacturer)
ProAmatine, scored (Shire)
Route of Administration
Oral
Dosage Form
Tablets
Strength
5 mg
Brand or Generic Name (Manufacturer)
Midodrine Hydrochloride Tablets (Available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name)
Route of Administration
Oral
Dosage Form
Tablets
Strength
5 mg
Brand or Generic Name (Manufacturer)
Orvaten (Upsher-Smith)
Route of Administration
Oral
Dosage Form
Tablets
Strength
5 mg
Brand or Generic Name (Manufacturer)
ProAmatine, scored (Shire)
Route of Administration
Oral
Dosage Form
Tablets
Strength
10 mg
Brand or Generic Name (Manufacturer)
Midodrine Hydrochloride Tablets (Available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name)
Route of Administration
Oral
Dosage Form
Tablets
Strength
10 mg
Brand or Generic Name (Manufacturer)
Orvaten (Upsher-Smith)
American Society of Health System Pharmacists; AHFS Drug Information 2010. Bethesda, MD. (2010), p. 1306

9 Safety and Hazards

9.1 Hazards Identification

9.1.1 Skin, Eye, and Respiratory Irritations

Eye, skin, ... and/or respiratory tract irritation.
United States Pharmacopeial Convention, Inc (USP); MSDS Database Online; Material Safety Data Sheet: Midodrine Hydrochloride; Catalog Number: 1443704; (Revision Date: January 19, 2010)

9.2 Fire Fighting

9.2.1 Fire Fighting Procedures

Water spray, dry chemical, carbon dioxide, or foam as appropriate for surrounding fire and materials. ... As with all fires, evacuate personnel to a safe area. firefighters should use self-contained breathing equipment and protective clothing.
United States Pharmacopeial Convention, Inc (USP); MSDS Database Online; Material Safety Data Sheet: Midodrine Hydrochloride; Catalog Number: 1443704; (Revision Date: January 19, 2010)

9.3 Accidental Release Measures

9.3.1 Cleanup Methods

Wear approved respiratory protection, chemically compatible gloves, and protective clothing. Wipe up spillage or collect spillage using a high- efficiency vacuum cleaner. Avoid breathing dust. Place spillage in appropriately labeled container for disposal. Wash spill site.
United States Pharmacopeial Convention, Inc (USP); MSDS Database Online; Material Safety Data Sheet: Midodrine Hydrochloride; Catalog Number: 1443704; (Revision Date: January 19, 2010)

9.3.2 Disposal Methods

SRP: Expired or waste pharmaceuticals shall carefully take into consideration applicable DEA, EPA, and FDA regulations. It is not appropriate to dispose by flushing the pharmaceutical down the toilet or discarding to trash. If possible return the pharmaceutical to the manufacturer for proper disposal being careful to properly label and securely package the material. Alternatively, the waste pharmaceutical shall be labeled, securely packaged and transported by a state licensed medical waste contractor to dispose by burial in a licensed hazardous or toxic waste landfill or incinerator.
SRP: At the time of review, regulatory criteria for small quantity disposal are subject to significant revision, however, household quantities of waste pharmaceuticals may be managed as follows: Mix with wet cat litter or coffee grounds, double bag in plastic, discard in trash.

9.3.3 Preventive Measures

Airborne exposure should be controlled primarily by engineering controls such as general dilution ventilation, local exhaust ventilation, or process enclosure. Local exhaust ventilation is generally preferred to general exhaust because it can control the contaminant at its source, preventing dispersion into the work area. An industrial hygiene survey involving air monitoring may be used to determine the effectiveness of engineering controls. Effectiveness of engineering controls intended for use with highly potent materials should be assessed by use of nontoxic surrogate materials. local exhaust ventilation such as a laboratory fume hood or other vented enclosure is recommended, particularly for grinding, crushing, weighing, or other dust-generating procedures.
United States Pharmacopeial Convention, Inc (USP); MSDS Database Online; Material Safety Data Sheet: Midodrine Hydrochloride; Catalog Number: 1443704; (Revision Date: January 19, 2010)
This material is assumed to be combustible. As with all dry powders, it is advisable to ground mechanical equipment in contact with dry material to dissipate the potential buildup of static electricity.
United States Pharmacopeial Convention, Inc (USP); MSDS Database Online; Material Safety Data Sheet: Midodrine Hydrochloride; Catalog Number: 1443704; (Revision Date: January 19, 2010)
As a general rule, when handling USP Reference Standards, avoid all contact and inhalation of dust, mists, and/or vapors associated with the material. Wash thoroughly after handling.
United States Pharmacopeial Convention, Inc (USP); MSDS Database Online; Material Safety Data Sheet: Midodrine Hydrochloride; Catalog Number: 1443704; (Revision Date: January 19, 2010)
SRP: Wastewater from contaminant suppression, cleaning of protective clothing/equipment, or contaminated sites should be contained and evaluated for subject chemical or decomposition product concentrations. Concentrations shall be lower than applicable environmental discharge or disposal criteria. Alternatively, pretreatment and/or discharge to a permitted wastewater treatment facility is acceptable only after review by the governing authority and assurance that "pass through" violations will not occur. Due consideration shall be given to remediation worker exposure (inhalation, dermal and ingestion) as well as fate during treatment, transfer and disposal. If it is not practicable to manage the chemical in this fashion, it must be evaluated in accordance with EPA 40 CFR Part 261, specifically Subpart B, in order to determine the appropriate local, state and federal requirements for disposal.
For more Preventive Measures (Complete) data for Midodrine (7 total), please visit the HSDB record page.

9.4 Handling and Storage

9.4.1 Storage Conditions

Store in tight container as defined in the USP-NF. This material should be handled and stored per label instructions to ensure product integrity.
United States Pharmacopeial Convention, Inc (USP); MSDS Database Online; Material Safety Data Sheet: Midodrine Hydrochloride; Catalog Number: 1443704; (Revision Date: January 19, 2010)

9.5 Exposure Control and Personal Protection

9.5.1 Personal Protective Equipment (PPE)

For handling of laboratory scale quantities, a cloth lab coat is recommended. Where significant quantities are handled, work clothing may be necessary to prevent take-home contamination.
United States Pharmacopeial Convention, Inc (USP); MSDS Database Online; Material Safety Data Sheet: Midodrine Hydrochloride; Catalog Number: 1443704; (Revision Date: January 19, 2010)
Safety glasses with sideshields are recommended. Face shields or goggles may be required if splash potential exists or if corrosive materials are present. Approved eye protection (eg, bearing the ANSI Z87 or CAS stamp) is preferred. Maintain eyewash facilities in the work area.
United States Pharmacopeial Convention, Inc (USP); MSDS Database Online; Material Safety Data Sheet: Midodrine Hydrochloride; Catalog Number: 1443704; (Revision Date: January 19, 2010)
Where respirators are deemed necessary to reduce or control occupational exposures, use NIOSH-approved respiratory protection and have an effective respirator program in place.
United States Pharmacopeial Convention, Inc (USP); MSDS Database Online; Material Safety Data Sheet: Midodrine Hydrochloride; Catalog Number: 1443704; (Revision Date: January 19, 2010)

9.6 Regulatory Information

9.6.1 FDA Requirements

The Approved Drug Products with Therapeutic Equivalence Evaluations List identifies currently marketed prescription drug products, including midodrine hydrochloride, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act. /Midodrine hydrochloride/
DHHS/FDA; Electronic Orange Book-Approved Drug Products with Therapeutic Equivalence Evaluations. Available from, as of November 11, 2010: https://www.accessdata.fda.gov/scripts/cder/ob/docs/queryai.cfm

9.7 Other Safety Information

9.7.1 Toxic Combustion Products

Emits foxic fumes under fire conditions.
United States Pharmacopeial Convention, Inc (USP); MSDS Database Online; Material Safety Data Sheet: Midodrine Hydrochloride; Catalog Number: 1443704; (Revision Date: January 19, 2010)

10 Toxicity

10.1 Toxicological Information

10.1.1 Drug Induced Liver Injury

Compound
midodrine
DILI Annotation
No-DILI-Concern
Label Section
No match
References

M Chen, V Vijay, Q Shi, Z Liu, H Fang, W Tong. FDA-Approved Drug Labeling for the Study of Drug-Induced Liver Injury, Drug Discovery Today, 16(15-16):697-703, 2011. PMID:21624500 DOI:10.1016/j.drudis.2011.05.007

M Chen, A Suzuki, S Thakkar, K Yu, C Hu, W Tong. DILIrank: the largest reference drug list ranked by the risk for developing drug-induced liver injury in humans. Drug Discov Today 2016, 21(4): 648-653. PMID:26948801 DOI:10.1016/j.drudis.2016.02.015

10.1.2 Interactions

It appears possible, although there is no supporting experimental evidence, that the high renal clearance of desglymidodrine (a base) is due to active tubular secretion by the base-secreting system also responsible for the secretion of such drugs as metformin, cimetidine, ranitidine, procainamide, triamterene, flecainide and quinidine. Thus there may be a potential for drug-drug interaction with these drugs.
US Natl Inst Health; DailyMed. Current Medication Information for MIDODRINE HCL (midodrine hydrochloride) tablet (October 2010). Available from, as of November 17, 2010: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?id=31527
Midodrine hydrochloride has been used in patients concomitantly treated with salt-retaining steroid therapy (i.e., fludrocortisone acetate), with or without salt supplementation. The potential for supine hypertension should be carefully monitored in these patients and may be minimized by either reducing the dose of fludrocortisone acetate or decreasing the salt intake prior to initiation of treatment with midodrine hydrochloride. Alpha-adrenergic blocking agents, such as prazosin, terazosin and doxazosin, can antagonize the effects of midodrine hydrochloride.
US Natl Inst Health; DailyMed. Current Medication Information for MIDODRINE HCL (midodrine hydrochloride) tablet (October 2010). Available from, as of November 17, 2010: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?id=31527
The use of drugs that stimulate alpha-adrenergic receptors (e.g., phenylephrine, pseudoephedrine, ephedrine, phenylpropanolamine or dihydroergotamine) may enhance or potentiate the pressor effects of midodrine hydrochloride. Therefore, caution should be used when midodrine hydrochloride is administered concomitantly with agents that cause vasoconstriction.
US Natl Inst Health; DailyMed. Current Medication Information for MIDODRINE HCL (midodrine hydrochloride) tablet (October 2010). Available from, as of November 17, 2010: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?id=31527
When administered concomitantly with midodrine hydrochloride, cardiac glycosides may enhance or precipitate bradycardia, A.V. block or arrhythmia.
US Natl Inst Health; DailyMed. Current Medication Information for MIDODRINE HCL (midodrine hydrochloride) tablet (October 2010). Available from, as of November 17, 2010: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?id=31527
An episode of transient, severe hypertension occurring within 2 minutes of injection of 1% lidocaine with 1:100,000 U of epinephrine in a patient taking midodrine for orthostatic hypotension /is reported/. /It was/ hypothesize that the patient's autonomic nervous system was dangerously susceptible to the effect of local anesthetic when combined with the vasoactive systemic effect of midodrine. Surgeons should minimize the use of vasoconstrictors in patients treated with midodrine to avoid hypertensive complications.
Rizzi MD et al; Am J Otolaryngol 31 (1): 67-9 (2010)

10.1.3 Antidote and Emergency Treatment

Recommended general treatment, based on the pharmacology of the drug, includes ... administration of alpha-sympatholytic drugs (e.g., phentolamine).
US Natl Inst Health; DailyMed. Current Medication Information for MIDODRINE HCL (midodrine hydrochloride) tablet (October 2010). Available from, as of November 17, 2010: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?id=31527
/SRP:/ Immediate first aid: Ensure that adequate decontamination has been carried out. If patient is not breathing, start artificial respiration, preferably with a demand valve resuscitator, bag-valve-mask device, or pocket mask, as trained. Perform CPR if necessary. Immediately flush contaminated eyes with gently flowing water. Do not induce vomiting. If vomiting occurs, lean patient forward or place on the left side (head-down position, if possible) to maintain an open airway and prevent aspiration. Keep patient quiet and maintain normal body temperature. Obtain medical attention. /Poisons A and B/
Currance, P.L. Clements, B., Bronstein, A.C. (Eds).; Emergency Care For Hazardous Materials Exposure. 3Rd edition, Elsevier Mosby, St. Louis, MO 2005, p. 160
/SRP:/ Basic treatment: Establish a patent airway (oropharyngeal or nasopharyngeal airway, if needed). Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with 0.9% saline (NS) during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 mL/kg up to 200 mL of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poisons A and B/
Currance, P.L. Clements, B., Bronstein, A.C. (Eds).; Emergency Care For Hazardous Materials Exposure. 3Rd edition, Elsevier Mosby, St. Louis, MO 2005, p. 160
/SRP:/ Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in severe respiratory distress. Positive-pressure ventilation techniques with a bag valve mask device may be beneficial. Consider drug therapy for pulmonary edema ... . Consider administering a beta agonist such as albuterol for severe bronchospasm ... . Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start IV administration of D5W /SRP: "To keep open", minimal flow rate/. Use 0.9% saline (NS) or lactated Ringer's if signs of hypovolemia are present. For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam or lorazepam ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poisons A and B/
Currance, P.L. Clements, B., Bronstein, A.C. (Eds).; Emergency Care For Hazardous Materials Exposure. 3Rd edition, Elsevier Mosby, St. Louis, MO 2005, p. 160-1

10.1.4 Human Toxicity Excerpts

/SIGNS AND SYMPTOMS/ Symptoms of overdose could include hypertension, piloerection (goosebumps), a sensation of coldness and urinary retention.
US Natl Inst Health; DailyMed. Current Medication Information for MIDODRINE HCL (midodrine hydrochloride) tablet (October 2010). Available from, as of November 17, 2010: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?id=31527
/CASE REPORTS/ A 42-year-old female had suffered from repeated syncope. She had vasovagal syncope with convulsions from vasodilatation and cardiac standstill which lasted for 9.8 sec. The 60 degrees head-up tilt test, nitroglycerin injection and isoproterenol infusion provoked vasovagal reaction. Although a beta blocker was not effective in preventing tilt-induced hypotension and bradycardia, midodrine hydrochloride (alpha-1 stimulant) or atropine prevented it. In this patient, insufficient constriction of capacitance vessels might have played an important role in activation of an inhibitory reflex from cardiopulmonary mechanoreceptors which caused hypotension and bradycardia.
Koyama S et al; Jpn Circ J 56 (9): 950-4 (1992)
/CASE REPORTS/ There are 2 reported cases of overdosage with midodrine hydrochloride, both in young males. One patient ingested midodrine hydrochloride drops, 250 mg, experienced systolic blood pressure greater than 200 mm Hg, was treated with an IV injection of 20 mg of phentolamine and was discharged the same night without any complaints. The other patient ingested 205 mg of midodrine hydrochloride (41 5-mg tablets) and was found lethargic and unable to talk, unresponsive to voice but responsive to painful stimuli, hypertensive and bradycardic. Gastric lavage was performed and the patient recovered fully by the next day without sequelae. The single doses that would be associated with symptoms of overdosage or would be potentially life-threatening are unknown.
US Natl Inst Health; DailyMed. Current Medication Information for MIDODRINE HCL (midodrine hydrochloride) tablet (October 2010). Available from, as of November 17, 2010: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?id=31527
/CASE REPORTS/ Midodrine is an alpha-agonist that causes peripheral vasoconstriction, resulting in increased blood pressure. It has been reported to be safe and effective in patients with end stage renal disease (ESRD) and is widely used for hemodialysis-associated hypotension. We report a case report of midodrine-induced ischemia in a patient on hemodialysis and review the literature relating to the safety of midodrine in patients with end stage renal disease.
Rubinstein S et al; Ren Fail 30 (8): 808-12 (2008)
For more Human Toxicity Excerpts (Complete) data for Midodrine (8 total), please visit the HSDB record page.

10.1.5 Non-Human Toxicity Excerpts

/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ Midodrine hydrochloride increased the rate of embryo resorption, reduced fetal body weight in rats and rabbits and decreased fetal survival in rabbits when given in doses 13 (rat) and 7 (rabbit) times the maximum human dose based on body surface area (mg/sq m). No teratogenic effects have been observed in studies in rats and rabbits.
US Natl Inst Health; DailyMed. Current Medication Information for MIDODRINE HCL (midodrine hydrochloride) tablet (October 2010). Available from, as of November 17, 2010: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?id=31527

10.1.6 Non-Human Toxicity Values

LD50 Mouse oral 675 mg/kg
US Natl Inst Health; DailyMed. Current Medication Information for MIDODRINE HCL (midodrine hydrochloride) tablet (October 2010). Available from, as of November 17, 2010: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?id=31527
LD50 Rat oral 30 to 50 mg/kg
US Natl Inst Health; DailyMed. Current Medication Information for MIDODRINE HCL (midodrine hydrochloride) tablet (October 2010). Available from, as of November 17, 2010: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?id=31527
LD50 Dog oral 125-160 mg/kg
United States Pharmacopeial Convention, Inc (USP); MSDS Database Online; Material Safety Data Sheet: Midodrine Hydrochloride; Catalog Number: 1443704; (Revision Date: January 19, 2010)

10.1.7 Populations at Special Risk

Midodrine hydrochloride is contraindicated in patients with severe organic heart disease, acute renal disease, urinary retention, pheochromocytoma or thyrotoxicosis. Midodrine hydrochloride should not be used in patients with persistent and excessive supine hypertension.
US Natl Inst Health; DailyMed. Current Medication Information for MIDODRINE HCL (midodrine hydrochloride) tablet (October 2010). Available from, as of November 17, 2010: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?id=31527

11 Associated Disorders and Diseases

12 Literature

12.1 Consolidated References

12.2 NLM Curated PubMed Citations

12.3 Springer Nature References

12.4 Thieme References

12.5 Chemical Co-Occurrences in Literature

12.6 Chemical-Gene Co-Occurrences in Literature

12.7 Chemical-Disease Co-Occurrences in Literature

13 Patents

13.1 Depositor-Supplied Patent Identifiers

13.2 WIPO PATENTSCOPE

13.3 Chemical Co-Occurrences in Patents

13.4 Chemical-Disease Co-Occurrences in Patents

13.5 Chemical-Gene Co-Occurrences in Patents

14 Interactions and Pathways

14.1 Chemical-Target Interactions

14.2 Drug-Drug Interactions

14.3 Drug-Food Interactions

Take with or without food. The absorption is unaffected by food.

15 Biological Test Results

15.1 BioAssay Results

16 Classification

16.1 MeSH Tree

16.2 NCI Thesaurus Tree

16.3 ChEBI Ontology

16.4 KEGG: ATC

16.5 KEGG: Target-based Classification of Drugs

16.6 KEGG: Drug Groups

16.7 WHO ATC Classification System

16.8 FDA Pharm Classes

16.9 ChemIDplus

16.10 ChEMBL Target Tree

16.11 UN GHS Classification

16.12 NORMAN Suspect List Exchange Classification

16.13 CCSBase Classification

16.14 EPA DSSTox Classification

16.15 MolGenie Organic Chemistry Ontology

17 Information Sources

  1. CAS Common Chemistry
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    https://creativecommons.org/licenses/by-nc/4.0/
  2. ChemIDplus
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    https://pubchem.ncbi.nlm.nih.gov/source/ChemIDplus
  3. DrugBank
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    https://www.drugbank.ca/legal/terms_of_use
  4. EPA DSSTox
    CompTox Chemicals Dashboard Chemical Lists
    https://comptox.epa.gov/dashboard/chemical-lists/
  5. European Chemicals Agency (ECHA)
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    https://echa.europa.eu/web/guest/legal-notice
  6. FDA Global Substance Registration System (GSRS)
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    https://www.fda.gov/about-fda/about-website/website-policies#linking
  7. Hazardous Substances Data Bank (HSDB)
  8. Human Metabolome Database (HMDB)
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    http://www.hmdb.ca/citing
  9. CCSbase
    CCSbase Classification
    https://ccsbase.net/
  10. ChEBI
  11. FDA Pharm Classes
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  12. NCI Thesaurus (NCIt)
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  13. Open Targets
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    https://platform-docs.opentargets.org/licence
  14. ChEMBL
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    http://www.ebi.ac.uk/Information/termsofuse.html
  15. ClinicalTrials.gov
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    https://clinicaltrials.gov/ct2/about-site/terms-conditions#Use
  16. Comparative Toxicogenomics Database (CTD)
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    http://ctdbase.org/about/legal.jsp
  17. Drug Gene Interaction database (DGIdb)
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    http://www.dgidb.org/downloads
  18. Therapeutic Target Database (TTD)
  19. Drug Induced Liver Injury Rank (DILIrank) Dataset
    LICENSE
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    https://www.fda.gov/about-fda/about-website/website-policies#linking
  20. Drugs@FDA
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    https://www.fda.gov/about-fda/about-website/website-policies#linking
  21. NORMAN Suspect List Exchange
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    Data: CC-BY 4.0; Code (hosted by ECI, LCSB): Artistic-2.0
    https://creativecommons.org/licenses/by/4.0/
    MIDODRINE
    NORMAN Suspect List Exchange Classification
    https://www.norman-network.com/nds/SLE/
  22. EU Clinical Trials Register
  23. Japan Chemical Substance Dictionary (Nikkaji)
  24. KEGG
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    https://www.kegg.jp/kegg/legal.html
    Anatomical Therapeutic Chemical (ATC) classification
    http://www.genome.jp/kegg-bin/get_htext?br08303.keg
    Target-based classification of drugs
    http://www.genome.jp/kegg-bin/get_htext?br08310.keg
  25. Metabolomics Workbench
  26. NLM RxNorm Terminology
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    https://www.nlm.nih.gov/research/umls/rxnorm/docs/termsofservice.html
  27. PharmGKB
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    https://www.pharmgkb.org/page/policies
  28. Pharos
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    https://pharos.nih.gov/about
  29. Springer Nature
  30. Thieme Chemistry
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    https://creativecommons.org/licenses/by-nc-nd/4.0/
  31. WHO Anatomical Therapeutic Chemical (ATC) Classification
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    https://www.nlm.nih.gov/copyright.html
    Adrenergic alpha-1 Receptor Agonists
    https://www.ncbi.nlm.nih.gov/mesh/68058646
  35. PubChem
  36. GHS Classification (UNECE)
  37. MolGenie
    MolGenie Organic Chemistry Ontology
    https://github.com/MolGenie/ontology/
  38. PATENTSCOPE (WIPO)
  39. NCBI
CONTENTS